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Objective: to present the experience of diagnosis, management and therapy with interleukin-1 inhibitors (iIL1) in patients with Chronic Infantile Onset Neurologic Cutaneous Articular/Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID) according to the Russian Federal Rheumatological Center data.Material and methods. From 2007 to 2023, eight patients were included in the study (7 men) aged 10 months to 33 years, including 3 with a disease duration of more than 10 years (13, 17 and 33 years). Genetic testing was performed in all patients and mutations in the NLRP3 gene were identified in 6 cases.Results and discussion. The age of onset of the disease ranged from 0 to 6 months. The delay in diagnosis and prescription of therapy ranged from 10 months to 33 years. All patients had the classic manifestations of CINCA/NOMID, including fever, rash, central nervous system (CNS) involvement, elevated ESR and CRP levels, 6 patients had articular manifestations, 7 had ocular manifestations and 6 had sensorineural hearing loss. Amyloidosis was detected in 1 case. All patients were prescribed iIL1. Anakinra was used in 6 patients (in 5 as the first line, in 1 as the second line therapy) with a positive response; subsequently 2 of these patients were switched to canakinumab once every 4 weeks (1 patient deteriorated and was readministered anakinra). Five patients received canakinumab (3 as first-line therapy, 2 as second-line therapy), 1 patient was switched to anakinra due to insufficient CNS response. The response to iIL1 therapy was positive in all patients, but incomplete in some of them due to the severity of the manifestations and the presence of irreversible organ damage.Conclusion. Patients with CINCA/NOMID have a severe disease and a poor prognosis. In this context, early administration of iIL1 is necessary. In the case of CNS involvement, the use of anakinra is preferable, as it is characterized by better penetration of the blood-brain barrier and is therefore more effective. Later it is possible to switch the patient to canakinumab, however, to achieve a complete response, it is sometimes necessary to increase the dose of the drug and reduce the interval between doses.

Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease of unknown etiology characterized by clinical manifestations such as fever, non-stable maculopapular rash, arthritis and/or arthralgias and leukocytosis with neutrophilia.Objective: to analyze the spectrum of clinical manifestations of AOSD and pharmacotherapy in real clinical practice.Material and methods. A cross-sectional study included 111 patients with a confirmed diagnosis of AOSD according to the Yamaguchi criteria, who were treated in two large Russian centers from 2019 to 2022: V.A. Nasonova Research Institute of Rheumatology (Moscow) and Almazov National Medical Research Centre (Saint Petersburg).Results and discussion. We analyzed the spectrum of clinical manifestations throughout the course of the disease. The spectrum of clinical manifestations of AOSD in our study was shown to be similar to the results of other studies. It was found that the frequency of the different clinical manifestations did not differ significantly.The majority of patients (74%) in our cohort received glucocorticosteroids (GC) in combination with disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs (bDMARDs). Monotherapy with GC was used in only 9% of patients. Up to 80% of patients received methotrexate (MTX) at various stages of the disease. For the treatment of patients refractory to GC and MTX therapy, bDMARDs were prescribed (44% of cases), most frequently interleukin-6 inhibitors (34%). In the St. Petersburg cohort, 13 (31.7%) of 41 patients were taking colchicine, which enabled control of disease manifestations and a reduction in the need for GC in 9 of them.Conclusion. Thus, we can draw a preliminary conclusion about the presence of steroid dependence in patients with AOSD. Up to 79.3% of AOSD patients are forced to take GC for a long period of time, which is associated with the risk of complications. Further studies on the optimal profile of bDMARDs are needed, as well as the role of colchicine as a potential therapeutic option for certain clinical and immunological subtypes of AOSD.

The aim – to present the experience of diagnosis, management, and therapy with IL-1 inhibitors in patients with Schnitzler’s syndrome (SchS) according to a multicenter Russian cohort.Materials and methods. In an observational retrospective study for a 10-year period (2012–2022), 17 patients with SchS who were admitted to the hospital or were observed on an outpatient basis, among them 8 women, 9 men, were included in the study. The diagnosis of all corresponded to the Strasbourg diagnostic criteria.Results. The age of patients ranged from 25 to 81 years (Me 53 [46; 56] years). The age at the time of the onset of the disease ranged from 20 to 72 years (Me 46 [39; 54] years), the duration of the disease before diagnosis ranged from 1 to 35 years (Me 6.5 [3; 6] years), in 3 it exceeded 10 years, in the rest it ranged from 1 to 8 years. Infectious and lymphoproliferative diseases, monogenic AIDS (CAPS, TRAPS, HIDS) were excluded from all patients at the prehospital stage. The guiding diagnosis for all was Still’s disease in adults. Clinical manifestations of the disease included: fatigue, lethargy, fatigue, rash and fever in all, skin elements were urticular in all, accompanied by itching in 6 (37.5%). Bone pain had 12 (70.6%), arthralgia – 16 (94.1%), arthritis – 9 (52.9%), myalgia – 7 (41.2%), weight loss in 4 (23.5%). Lymphadenopathy (6), enlarged liver (6), pericarditis (4), angioedema (6), redness and dryness in the eyes (3), sore throat (2), abdominal pain (1), distal polyneuropathy (2), paraesthesia (1), chondritis of the auricles were less common (1). Monoclonal gammopathy was detected in all with a secretion level of 2.9–15.1 g/l: IgMk (n=10 (64.7%)), less often IgMλ (n=2), IgGk (n=2), IgGλ (n=1), IgAλ (n=1). Ben-Jones protein was not detected in any of them. All patients had an increase in the level of ESR, CRP. 16 patients before inclusion in the study received GC (94.1%) with a temporary effect and its escape with dose reduction or cancellation, DMARD – 7, among them methotrexate (5), hydroxychloroquine (2), cyclophosphamide (1), also NSAIDs and antihistamines in all, biological drugs: anti-B-cell the drug rituximab (1), monoclonal AT to IgE – omalizumab in 2 (1 – without effect, 1 – partial effect). 11 patients were prescribed IL-1: canakinumab – 9 (52.9%) subcutaneously once every 8 weeks, anakinra – 4 (23.5%) subcutaneously daily. The duration of taking anakinra, which was prescribed in the test mode, ranged from 1 week to 2.5 months with a further switch to canakinumab in 3. The duration of taking canakinumab at the time of analysis ranged from 7 months to 8 years. Against the background of treatment with IL-1, 10 out of 11 (90.9%) received a complete response from the clinical manifestations of the disease and a decrease in the level of ESR and CRP within a few days. In 1 patient, a partial response was received to the administration of anakinra, and when switching to canakinumab, the effect of treatment was finally lost. 1 patient received IL-6 for 8 months with incomplete effect and transition to IL-1 with positive dynamics. In 1 patient, due to the persistent absence of relapses, the interval between canakinumab injections was increased to 5 months without signs of reactivation, but subsequently, against the background of stress and relapses of the disease, the intervals were reduced to 4 months. A healthy child was born in the same patient on the background of treatment. The tolerability of therapy was satisfactory in all patients, no SAE was noted.Conclusion. SchS is a rare multifactorial/non–monogenic AID that needs to be differentiated from a number of rheumatic diseases and other AIDS. The onset in adulthood, the presence of recurrent urticarial rashes in combination with fever and other manifestations of a systemic inflammatory response are indications for examination for monoclonal secretion. The use of short- or long-acting IL-1 is a highly effective and safe option in the treatment of such patients.

This article presents review of literature of the history of international classification criteria of American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) 2016, considers the features of validation and development of preliminary European criteria 1993, criteria of American European Consensus Group (AECG) 2002 and ACR 2012 criteria.

This article presents the first case of VEXAS syndrome identified in the Russian Federation as well as characteristics of currently known clinical manifestations and treatment approaches. The clinical observation described is an impressive example of how the identification of a new pathogenic mutation can change the understanding of the classification, diagnosis and treatment of previously known immunoinflammatory diseases. Thus, in refractory forms of relapsing polychondritis, neutrophilic dermatosis, atypical forms of vasculitis, inflammatory joint diseases or undifferentiated systemic inflammatory syndrome, especially when associated with macrocytic anemia and myelodysplastic syndrome, VEXAS syndrome should be suspected and genetic testing should be performed to exclude the autoinflammatory nature of the existing condition.

In recent years, more and more data have emerged confirming the contribution of non-HLA genetic markers to the predisposition to thedevelopment of Sjögren's syndrome (SS) and its severe complication, MALT-lymphoma. Objective: to study the association of polymorphisms of IRF5 (rs2004640), STAT4 (rs7574865), and TNFAIP3 (rs6920220, rs2230926) genes with predisposition to the development of SS and MALT-lymphoma. Materials and methods. The study included 80 patients with SS and 103 individuals in the control group. Sixteen patients were diagnosed with MALT-lymphoma. Genotyping of polymorphisms of IRF5 (rs2004640), STAT4 (rs7574865), TNFAIP3 (rs6920220, rs2230926) genes was performed by real-time polymerase chain reaction using original allele-specific probes labeled with different fluorescent labels. Results and discussion. The distribution of genotypes and alleles of the STAT4 gene differed statistically significantly in the study and control groups of patients (p = 0.0005 and p = 0.0001, respectively). The presence of the homozygous TT genotype increased the risk of developing SS more than eightfold compared to TG+GG genotypes (odds ratio, OR=8.2; 95 % confidence interval, CI 2.5–30.0; p=0.0001)]. The polymorphism of the TNFAIP3 rs2230926 gene was also associated with the risk of developing SS: the presence of the TG genotype significantly increased the probability of developing SS compared to the TT genotype (OR 6.4; 95% CI 1.2–44.3; p = 0.01). The development of MALT-lymphoma was associated with the rs6920220 polymorphism of the TNFAIP3 gene. In 10 out of 16 patients with MALT-lymphoma (62.5 %) at least one minor A allele (AA+GA) was detected, while in patients without MALT-lymphoma only in 32.8 % of patients at least one minor A allele was detected (OR=3.4, CI 1.1–10.7; p=0.03). In addition, a correlation was found between the rs7574865 TT genotype of the STAT4 gene and the risk of developing severe leukopenia in SS, which was significantly more frequent in carriers of the TT genotype than in individuals with the GG + GT genotype (OR 4.9; 95 % CI 1.7–14.4; p = 0.004). Polymorphism of the IRF5 gene (rs2004640) was not associated with risk of developing SS or with clinical manifestations of the disease. Conclusion. Polymorphisms rs7574865 of STAT4 gene, rs6920220, rs2230926 of TNFAIP3 gene are associated either with the risk of developing SS or with severe complications of the disease, MALT-lymphoma and leukopenia.

IgG4-related disease (IgG4-RD) is characterized by the appearance of tumor-like foci in one or more organs, occurring synchronously or metachronously, due to fibro-inflammatory changes with hypersecretion of immunoglobulin G subclass 4 (IgG4) in tissues and/or blood serum. Diabetes mellitus (DM) develops among 43-68% of patients with IgG4-related pancreatitis. Diabetes against the background of IgG4-RD can be caused both by damage to the endocrine part of the pancreas and the use of glucocorticosteroids, but its course is moderate, with a rare need for insulin therapy. In both cases, the use of genetically engineered biological therapy with rituximab may be accompanied by an improvement in carbohydrate metabolism. This article describes the course of diabetes and the need for hypoglycemic therapy for 1.5 years in a patient treated with IgG4-RD.

The article discusses the relevance of determining DNA double-strand breaks (DSBs) using the analysis of γ-H2AX foci as a marker of DNA instability in various conditions. The issues of the formation of DSBs and the peculiarities of their detection in various tissues are highlighted. Changes in the intensity of DSBs formation during the use of radiological diagnostic methods, stress, increased physical exertion, some oncological and rheumatic diseases, as well as the dynamics of DNA repair on the background of various methods of therapy were analyzed.

The article provides a literature review on the current understanding of respiratory tract damage in primary Sjögren’s syndrome (pSS) with an emphasis on interstitial lung disease (ILD), as well as approaches to the differential diagnosis, treatment, and screening of pSS-ILD.

Objective: to analyze the nosological spectrum, demographic, clinical and laboratory characteristics of diseases with a significant enlargementof major salivary (SG) / lacrimal glands, and/or accessory organs of the eye and paranasal sinuses lesions in rheumatological practice.Patients and methods. This work includes 73 patients who underwent a complex clinical and laboratory, imaging, pathomorphological and histomolecular examination, which was necessary to establish a nosological diagnosis. In all cases, the diagnosis was confirmed pathomorphologically.Results and discussion. Sjogren's syndrome (SjS) was diagnosed in 30 (41%) patients (14 of them developed lymphoproliferative disorder, LPD, as a complication), granulomatosis with polyangiitis (GPA) – in 12 (16.4%), IgG4-related disease (IgG4-RD) – in 10 (13.7%), sarcoidosis – in 6 (8.2%), non Langerhans cell histiocytosis – in 2 (2.7%), AL-amyloidosis – in 1 (1.4%), Warthin's tumor – in 1 (1.4%), chronic atrophic rhinitis – in 1 (1.4%), infectious lesions – in 3 (4.1%) (HIV-associated – in 2, dirofilariasis – in 1), idiopathic inflammatory pseudotumor – in 6 (8.2%). In 1 (1.4%) patient, the diagnosis could not be established.A massive increase of major SG was observed in 46 patients, more often (in 28 cases) with SjS with LPD or without it, with IgG4-RD (in 7) and sarcoidosis (in 6). Orbital lesions were observed in 18 patients: in 7 with IgG4-RD, in 5 with idiopathic inflammatory pseudotumor, in 2 with sarcoidosis, in 2 with GPA, and in 1 each with non Langerhans cell histiocytosis and dirofilariasis. Nasal lesions in the form of chronic rhinosinusitis with or without nasal septum perforation, were found in 18 patients, 12 of whom suffered GPA and 6 – IgG4-RD.Two algorithms, that can facilitate the choice of additional studies and the direction of diagnostic search have been proposed for practicing rheumatologists.Conclusion. Taking into account the possible similarity of clinical manifestations of the diseases with the formation of mass-like tissue, the differential diagnosis should be based on pathomorphological study.

The materials of the Russian NIIR/ARP-COVID-19 database, which included adult (over 18 years old) patients with immuno-inflammatory rheumatic diseases (IIRD) who underwent COVID-19 (coronavirus disease 2019), and a literature review concerning the course and outcomes of COVID-19 in patients with these diseases, are presented. From July 17, 2020 to April 23, 2021, 156 messages were received and analyzed. The study group was represented mainly by women (75%). The average age of patients was 52.0±14.8 years, of which 53 (33.9%) patients were aged 60 years and older. The most frequent clinical manifestations of COVID-19 were fever (62.2%), cough (40.4%), anosmia (37.8%), shortness of breath (33.3%). During the course of COVID-19, computed tomography of the chest organs was performed in 143 patients. When assessed on an “empirical” visual scale, stage 0 of lung lesion was observed in 49 (34.3%) patients, stage 1 in 40 (28%), stage 2 in 35 (24.5%), stage 3 in 19 (13.2%), stage 4 in 0. In the study group, a favorable outcome was observed in 137 (97.9%) patients. Fatal outcome was registered in 3 patients. The effect of COVID-19 on the course of IIRD was assessed in 131 patients: in 52 (39.7%) patients, the course of IIRD worsened, in 1 (0.8%) it improved, in 78 (59.5%) there was no effect. Literature data on the risk of infection with the SARS-CoV-2 virus, the course and outcomes of COVID-19 in rheumatic and musculoskeletal diseases are contradictory, which dictates the need to continue collecting data on the rheumatological problems of COVID-19 in the Russian patient population, taking into account international experience.

The article discusses the importance of ultrasound examination of the salivary glands in Sjogren’s disease for the diagnosis, as well as for assessing the activity of the disease. The characteristics of the main ultrasound changes in the salivary glands and the pathogenetic reasons of these changes are given. The results of studies of the dynamics of changes in ultrasound parameters both in patients not receiving treatment and in the presence of various methods of therapy are presented. The paper also provides basic data on the role of ultrasound in the differential diagnosis of diseases involving the salivary glands.

Objective: to determine the frequency, spectrum and severity of liver affection in anti-centromere antibodies (ACA) positive patients with primary Sjogren's syndrome (pSS).Patients and methods. 119 ACA-positive patients with pSS were included in the study, 37 (31%) of them had signs of liver damage, 3 of these patients were excluded from the study (2 had cholelithiasis, 1 had viral hepatitis B). Signs of autoimmune liver damage were found in 34 (28.6%) patients, most of them were seropositive for antimitochondrial antibodies (AMA). The diagnosis of primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) was established according to the recommendations of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association and the Russian Society for the Study of the Liver. In 5 (14.7%) patients the cause of cholestasis remained unspecified.Results and discussion. AMA were found in 73.5% of patients, elevated serum IgM levels – in 57.6%. Clinically liver damage in most cases was characterized by an asymptomatic, slowly progressive course without a dramatic increase of symptoms over time. Liver cirrhosis was found in 14.7% of patients. According to clinical, laboratory and morphological manifestations, PBC was diagnosed in 21 patients, 4 of them also had a cross syndrome with AIH. AMA-negative PBC was found in 3 patients and isolated AIH – in 1. In most cases, histological stage I of PBC was detected. During follow-up, median of 7 years (range from 2 to 15 years), in 7 patients with stage I PBC and in 7 AMA-positive patients without functional liver disorders no clinical, laboratory or instrumental progression of liver damage was noted. In this regard, it was suggested that these patients have epitheliitis of the biliary ducts as manifestation of glandular affection in pSS, and not true PBC.Conclusion. Autoimmune liver lesions are detected in 28.6% of ACA-positive patients with pSS, most (41.2%) of them develop epitheliitis of the biliary ducts as pSS manifestation or a combination of pSS with PBC (with the same frequency), less often PBC / AIH cross syndrome is diagnosed. PBC / pSS-related epitheliitis of the biliary ducts in ACA-positive patients is characterized by a slowly progressive asymptomatic course in most cases and rarely leads to the development of liver cirrhosis.

Objective: to compare clinical and laboratory manifestations in 2 groups of patients with primary Sjogren’s syndrome (pSS): with and without anticentromere antibodies (ACA); compare the incidence, clinical and laboratory characteristics of lymphomas in these two groups.Materials and methods. We examined 119 patients with ACA-positive pSS (pSS-ACA+). pSS was diagnosed based on Russian 2001 criteria, systemic sclerosis (SSc) – criteria ACR/EULAR 2013. To diagnose liver diseases, the level of transaminases, alkaline phosphatase and antimitochondrial antibodies (AMA) was determined, as well as liver biopsy. The diagnosis of primary biliary cholangitis (PBC) was established according to the recommendations of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association and the Russian Society for the Study of the Liver. Lymphomas were diagnosed according to histological, immunohistochemical and molecular studies of affected organs biopsies, according to the classification of the World Health Organization. A combination of pSS and SSc was diagnosed in 37 patients, and they were excluded from further analysis. We compared clinical and laboratory features in patients with pSS-ACA+ (n=82) and ACA-negative pSS (pSS-ACA–, n=64) and characterized lymphomas in the pSS-ACA+ (n = 14) and pSS-ACA– (n=10) groups.Results and discussion. In patients with pSS-ACA+, a later age of disease onset was revealed, the duration of the disease before lymphoma development did not differ. In patients with pSS-ACA+, we found a lower frequency of rheumatoid factor (RF), antibodies to Ro (anti-Ro) and La (anti-La), decreased C3-complement, hypergammaglobulinemia, increased IgG concentration, CRP, increased ESR, leukopenia and anemia. 51.2% of patients with pSS-ACA+ were seronegative for anti-Ro, anti-La and RF. Patients with pSS-ACA+ had a higher frequency of AMA and elevated IgM. The incidence of cryoglobulinemia and paraproteinemia did not differ. The frequency of recurrent parotitis in pSS-ACA+ was significantly lower, there were no differences in the frequency and severity of other signs of salivary and lacrimal gland damage. PBC and epitheliitis of the biliary ducts in patients with pSS-ACA+ were detected significantly more often. Damage to the peripheral nervous system, lungs, hypergammaglobulinemic purpura, arthralgia and autoimmune thyroiditis were significantly more often detected in the group of patients with pSS-ACA–. In the pSS-ACA+ group, Raynaud’s phenomenon was significantly more frequent, mainly with scleroderma-type capillaroscopic abnormalities. There was no difference in the frequency of other signs characteristic of SSc. MALT lymphomas were diagnosed in the study groups with the same frequency. Patients with lymphomas in the pSS-ACA+ group were characterized by significantly higher laboratory activity. All patients with lymphomas in both groups showed persistent parotid salivary gland enlargement. Lymphomas in both groups developed in patients with late stage salivary and lacrimal gland damage, systemic manifestations of pSS in both groups were rare.Conclusion. pSS-ACA+ is an independent subtype of pSS, which has a number of significant clinical and laboratory differences from the “classic” variant of the disease. ACA in pSS are associated with a low frequency of anti-Ro, anti-La, and RF, as well as an increased risk of PBC and limited SSc. MALT lymphomas in the pSS-ACA+ and pSS-ACA– groups developed with the same frequency and were associated with the progression of glandular damage, regardless of the presence of systemic manifestations.

Aseptic necrosis of bone is a serious disease that, if detected early and with adequate therapy, can be cured. Late diagnosis and lack of therapy leads to rapid joint destruction and patient disability. The proposed draft guidelines are a part of the National Clinical Guidelines for Aseptic Bone Necrosis (Osteonecrosis). Purpose of the study was creating an algorithm for diagnosing and treating osteonecrosis based on assessment of the level of evidence of literature data. The Guidelines reflect aspects of the clinical, instrumental and laboratory examination of patients with osteonecrosis, treatment options depending on the localization of the process and stage of the disease.

Objective: to study clinical and laboratory features in patients with anticentromere antibody (ACA)-positive SjЪgren's disease (SD), as well as the sensitivity of different methods for determination of ACA, and to elaborate an algorithm for differential diagnosis in ACA-positive patients.Patients and methods. The V.A. Nasonova Research Institute of Rheumatology followed up 136 patients who were highly positive for ACA. The investigators used the 2001 Russian criteria for the diagnosis for SD; the 2013 ACR/European League Against Rheumatism (EULAR) criteria for that of scleroderma systematica (SDS); the guidelines of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association, and the Russian Society for the Study of the Liver for that of primary biliary cholangitis (PBC)/biliary duct epitheliitis in the presence of SD. Lymphomas were diagnosed by biopsies of affected organs according to the WHO classification. SD was diagnosed in 119 patients; SDS in 49 cases (37 with SDS concurrent with SD and 12 with isolated SDS), PBC/biliary duct epitheliitis in 23 (all cases with PBC/biliary duct epitheliitis concurrent with SD and/or SDS); 5 patients were excluded from the investigation. Further analysis included 131 ACA-positive patients. The patients were divided into three groups: SD (n=82 or 62.6%); SD+SDS (n=37 or 28.24%); SDS (n=12 or 9.16%).Results and discussion. Autoantibodies to centromere peptide (CENP) A and CENP-B in the same titers were detected in all ACA-positive patients, regardless of diagnosis. Comparative analysis of three patient groups revealed no statistically significant differences in the frequency of laboratory deviations. The signs characteristic of classical SD (rheumatoid factor (RF)), anti-Ro and anti-La antibodies, leukopenia, higher ESR values, hypergammaglobulinemia, and elevated IgG/IgA levels) were found in a small proportion of patients. The frequency and severity of glandular manifestations did not differ in SD and SD + SDS. PBC/biliary duct epitheliitis was present in 17.5% of ACA-positive patients (in most antimitochondrial antibody-positive cases); no statistically significant differences in its frequency were found between the groups. Other extraglandular manifestations in SD and SD + SDS were identified in a smaller number of patients. All sclerodermic spectrum manifestations were more common in SD and SD + SDS than in BS. Pulmonary arterial hypertension was not diagnosed in any patient from the SD group. MALT lymphomas were detected in 19 ACA-positive patients. Those were present only in BS patients and absent in the SDS group. MALT lymphomas developed in the first 10 years after the onset of SD. The transformation of MALT lymphoma into diffuse large B-cell lymphoma was observed in 2 patients. The main signs of lymphomas in SD patients were persistent parotid salivary gland enlargement, decreased levels of complement C4 and peripheral blood CD19+ cells, as well as cryoglobulinemic vasculitis, serum monoclonal secretion, lymphoid infiltration in the minor salivary glands (a focus score of >4), and severe damage to the salivary and lacrimal glands.Conclusion. ACA-associated SD is an independent disease subtype characterized by an increased risk for SDS, PBC, and MALT lymphomas and by a low frequency of the systemic manifestations and laboratory signs characteristic of classical SD. Regardless of the detected type of antibodies and the presence or absence of extraglandular manifestations, damage to the salivary and lacrimal glands progresses in SD, which often leads to lymphomas; therefore, the therapy that may prevent this complication should be initiated as soon as possible after SD diagnosis. The lymphoproliferation signs identified in this investigation should be taken into account in all ACA-positive patients with SD for the early diagnosis of lymphoid tumors before therapy is prescribed. An algorithm for differential diagnosis in seropositivity for ACA is presented. Determination of autoantibodies to CENP-A and CENP-B does not allow the differential diagnosis in ACA-positive patients.

Sjögren's disease (SD) is a chronic autoimmune disease characterized by lymphoplasmacytic infiltration of the exocrine glands, leading to the development of their destruction and progressive functional failure. The prevalence of SD is about 5%, which makes it one of the most common autoimmune diseases. SD often has a chronic, slowly progressing course.The paper discusses the results of international clinical trials of the efficiency of anti-B-cell therapy with rituximab (RTM) for glandular SD. It considers the impact of this therapy on various immunological, histological indicators, subjective and objective parameters of glandular function, and disease activity. Possible reasons for the discrepancy between the results of open-label clinical trials and randomized clinical trials, as well as predictors for the efficiency of RTM therapy are discussed.It has been found that RTM used to treat SD effectively reduces B-cell activity, improves the morphological pattern in the salivary glands and some extraglandular manifestations of the disease, and diminishes dryness and weakness. Anti-B-cell drugs have a great potential to treat SD.

Osteoarthritis (OA) and other large joint diseases remain an unsolved problem of modern orthopedics and rheumatology. The use of intra-articular injections of various drugs, including hyaluronic acid, is widespread in both our and foreign countries; however, the efficiency of treatment is not always sufficient, despite its high cost. One of the most effective and inexpensive methods for treating OA is intra-articular ozone therapy that has recently become widespread. The ability of ozone to suppress joint inflammation, to improve blood supply, including that to the subchondral bone, and to reduce pain is considered to be the main advantages of this method. The safety and low risk of adverse reactions allow ozone to be used in a wide range of patients.

Objective: to study the clinical and laboratory features of patients with anticentromere antibody (ACA) positive Sjö gren’s syndrome (SjS); to assess the spectrum of autoantibodies in patients of this group; to determine the frequency with which the SjS patients who are highly positive for ACA, meet the international classification criteria for SjS and systemic sclerosis (SS); to reveal the incidence of MALT lymphomas in this patient group; to estimate the incidence of primary biliary cirrhosis (PBC)/biliary lesions as part of autoimmune epithelitis in SjS in this patient group.Material and methods. A total of 83 patients with ACA positive SjS were comprehensively examined at the V.A. Nasonova Research Institute of Rheumatology during the period 2012 to 2018. The inclusion criteria were con formity to the 2001 Russian SjS criteria and a high ACA level. MALT lymphomas were diagnosed on the basis of histological and immunohistochemical studies and polymerase chain reaction-based determination of B-cell clonality in the biopsy samples of affected organs according to the World Health Organization classification of Hematopoietic Tumors. The diagnosis of PBC/biliary lesions was made on the basis of histological and immunohistochemical studies of liver biopsy specimens.Results and discussion. The investigation revealed low detection rates for anti-Ro antibodies (32.5%), anti-La antibodies (7.2%) and rheumatoid factor (RF) (21.7%), which were typical for the classical SjS immunophenotype), increased ESR (14%), leukopenia (7%), hypergammaglobulinemia (17.6%), elevated levels of IgG (9.5%) and IgA (18.7%), and hypocomplementemia (16.1%) in the ACA positive SjS patients. Despite the low detection rate of RF, 15 (18%) patients in this group developed MALT lymphomas: 14 patients had salivary gland MALT lymphoma and one patient had tonsil MALT lymphoma with peripheral lymph node involvement (generalized marginal zone lymphoma). Also, the patients of this group showed high detection rates for AMA antibodies (34.6%), increased IgM level (29.7%) and a higher risk for PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS (14.5%). AMA-antibodies were absent in only two patients who were diagnosed with liver disease according to biopsy specimens. Nervous system and renal lesions, antiphospholipid syndrome, rheumatoid arthritis, hypergammaglobulinemic purpura, and cryoglobulinemic vasculitis were much less common and sporadic. Also ACA-positive SjS patients often have Raynaud’s phenomenon (54.9%) with scleroderma-type capillaroscopic changes (68%) and a limited form of SS (24%) according to the 2013 ACR criteria.Conclusion. ACA-positive SjS is a subtype of the disease, which is significantly different from the classic one in a number of clinical and laboratory signs and characterized by an increased risk for SS, MALT lymphomas, and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS which in some cases leads to the underdiagnosis of SjS. ACA should be considered as pathogenetically related to SjS autoantibodies; and all patients who are seropositive for ACA should be examined for SjS and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS regardless of whether they have SS or not, as well as complaints of dry mouth and eyes. Patients with significantly enlarged salivary glands should undergo biopsy to rule out or confirm MALT lymphoma before initiating hormonal, antilymphoproliferative, and anti-B-cell therapy.

IgG4-related disease (IgG4-RD) is a systemic immune mediated condition that is characterized by the formation of tumor-like fibroinflamma-tory foci in different organs and by the elevation of serum and tissue IgG4 levels in the majority of patients. The pathogenesis of the disease, including the role of IgG4, has not been established exactly. Serum and tissue IgG4 hypersecretion is a nonspecific sign and occurs in many rheumatic, infectious, and malignant diseases.Objective: to determine the range of nosological entities associated with the increase in serum IgG4 levels, as well as the frequency and nature of this increase in patients with IgG4-RD.Patients and methods. The results of all serum IgG4 measurements carried out in the Laboratory of Immunology and Molecular Biology of Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, in 2017—2018 were analyzed. Serum IgG4 parameters were separately estimated in 52 patients with verified IgG4-RD according to the universal diagnostic criteria proposed by H. Umehara et al (2011).Results and discussion. In 2017—2018, a total of247patients were tested for serum IgG4 levels. The latter were elevated in 76 (30.8%) patients, but only 28 (36.8%) were diagnosed as having IgG4-RD. Along with IgG4-RD, antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) were characterized by increased serum IgG4 levels. The highest median IgG4 level was found in patients with a verified diagnosis of IgG4-RD: 6.31 vs 3.2, 3.22, and 2.69 g/L in ANCA-associated vasculitis, RA, and SLE, respectively.In 52 patients with IgG4-RD, the IgG4 level >1.35 g/L was found in 88% of cases. The median serum IgG4 level was 3.45 g/L (2.1; 11.4). The highest level was observed in patients with generalized lymphadenopathy and in those with IgG4-related sialoadenitis and dacryoadenitis (Mikulicz disease). The serum IgG4 level was positively correlated with the number of affected organs (Spearman's correlation coefficient, 0.39; p=0.0056, Student's t-test). All the patients showed a tendency towards decreasing serum IgG4 levels during treatment regardless of its clinical response; however, the levels returned to normal only in 73% after 12 months of treatment.Conclusion. The increased serum and tissue IgG4 concentration is not specific, but at the moment it is the only disease marker available in clinical practice. To correctly interpret the diagnosis, it is necessary to assess the entire set of clinical manifestations, imaging data, and morpholopathological findings.

The paper describes a clinical case of a female patient with bacterial sialadenitis. The specific features of this case are sialadenitis concurrent with serum monoclonal secretion, as well as the absence of the effect of previous antibacterial therapy. The author describes basic directions in the differential diagnosis of sialadenitis, which requires that rheumatic, granulomatous, and tumor diseases should be ruled out.

Regulatory T cells (Tregs) is a CD4+ lymphocyte subpopulation that maintains autotolerance by suppressing the activity of autoreactive lymphocytes. There is a hypothesis that functional defects or a smaller number of Tregs underlie the pathogenesis of a number of autoimmune diseases. The paper considers the main features of the phenotype of Tregs. It discusses the number of Tregs in both peripheral blood and affected organs in systemic lupus erythematosus, as well as the time course of changes in the level and functional abilities of different subpopulations of Tregs during immunosuppressive therapy. In addition, the paper presents various approaches to using Treg lymphocytes in the therapy of autoimmune diseases.

Objective. To evaluate the efficacy and safety of rituximab (RTM) treatment in the long-term follow-up of patients with systemic lupus erythematosus (SLE) refractory to standard therapy. Material and methods. RTM therapy was prescribed to 97 SLE patients with high disease activity and insufficient effica- cy of using high doses of glucocorticoids (GC) and cytostatics. The median follow-up time (25th; 75th percentiles) was 18 [12; 36] months. The most common clinical manifestations of SLE included nephritis (62%), skin lesion (33%), and lesion of the nervous system (22.7%). The clinical assessment of the SLE activity was carried out using the SLEDAI-2K activity index. In assessing the therapy efficacy, the following concepts were used: the partial response (PR), complete response (CR), and flare. Flare was classified as moderate (MF) and severe (SF) using the SLE flare index (SFI). Results. Immediately after RTM therapy, depletion of B-cells was determined in 78% of the patients with SLE. During the 6-year follow-up, the effect of RTM therapy was achieved in 84% of the patients after repeated courses of RTM (CR – 56%, PR – 28%). In total, flares were observed in 24 (24.7%) patients; the median interval from RTM administration to flare was 12 [12; 24] months. In the long-term follow-up, the decline in the SLEDAI-2K index, normalization of laboratory test values, and the decrease in the daily GC dose were noted. Most patients tolerated well both the first and repeated courses of RTM therapy. Conclusion. According to the results of the long-term follow-up, RTM therapy is a highly effective method to treat SLE patients with the ineffectiveness of previously conducted standard therapy with GC and cytostatics. Good tolerance of RTM treatment has been noted; no increase in risk of infectious complications or adverse reactions has been found.

This case is the first description of the successful anti-B-cell therapy with rituximab in a patient with Sjogrenʼs syndrome and neuromyelitis optica spectrum disorder in Russia. This article contains the literature data on clinical manifestations and methods of the diagnosis of neuromyelitis optica spectrum disorder. Furthermore, contemporary view on the pathogenesis of the combination of this disease with Sjogrenʼs syndrome are presented here.

AIM: To evaluate the impact of anti-B-cell therapy on the clinical and immunological parameters of systemic lupus erythematosus (SLE) activity, on the time course of changes in these parameters during long-term follow-up, and on the tolerability of repeated rituximab (RTM) therapy cycles/MATERIAL AND METHODS: RTM was given to 97 patients with high activity of SLE refractory to treatment with glucocorticosteroids (GCS) and cytostatics. The follow-up lasted 18 (12-36) months. The most common clinical manifestations of SLE were lupus nephritis (LN) (62%) and skin (33%) and nervous system (22.7%) involvements. Clinical SLE activity was assessed applying the SLE disease activity index 2000 (SLEDAI2K); therapeutic effectiveness was evaluated using indicators, such as partial response (PR), complete response (CR) and exacerbation. The exacerbation was classified as moderate and severe using the Selena-Sledai Flare index (SFI)/RESULTS: Depletion was identified in 78% of the patients with SLE immediately after RTM therapy. During 3.5 years of follow-up, the effect of RTM was seen in 82% of the patients after repeated RMT therapy cycles (CR 56% and PR 28%). Exacerbations were observed in a total of 24 (24.7%) patients; the exacerbation lasted 12 (12-24) months after RTM therapy: of them 17.5% with LN and 7.2% with extrahepatic manifestations of SLE (exacerbations occurred 12 (12-24) and 18 (6-48) months after RMT therapy). In 24 exacerbated patients, B cells recovered at 6 (3-12) months. A year after RMT therapy, a group of 35 patients who were observed to have complete B cell depletion achieved CR statistically significantly more frequently than a group of 20 patients who had B-cell recovery (65.7 and 30% respectively, p=0.03). CR was observed significantly more often in patients after repeated RTM therapy cycles than those who had received only one RTM therapy cycle (p=0.02). The long-term follow-up showed a reduction in SLEDAI2K, normalization of laboratory values, and a decrease in the daily dose of GCS. Most patients tolerated well both the first and repeated RTM therapy cycles/CONCLUSION: According to the results of the long-term follow-up, RTM therapy is a highly effective treatment option for SLE patients in whom the previous standard therapy with GCS and cytostatics was previously ineffective. The 3.5-year follow-up showed a good tolerability of RTM and revealed no increase in the risk of infectious complications or adverse reactions.

AIM: To determine the time course of changes in the blood levels of antibodies (Ab) to complement component C1q (a-C1q) in patients with systemic lupus erythematosus (SLE) during rituximab (RTM) therapy and the association with organ injuries in SLE/MATERIAL AND METHODS: The study involved 41 patients (3 men and 38 women; their median age was 27.5 (range 22-36) years) with definite SLE. Their blood a-C1q levels were determined by enzyme immunoassay. The levels and detection rates of a-C1q were estimated in relation to organ injuries, the time course of RTM therapy-induced changes in a-C1q levels were determined. High-positive (>30 U/ml), low-positive (10-30 U/ml), and negative (≤10 U/ml) a-C1q levels were found/RESULTS: A-C1q was detected in 19 (46.3%) patients with different clinical manifestations of SLE. The patients with renal diseases had high-positive levels of a-C1q statistically significantly more frequently than those without renal involvement (p=0.04). Low-positive and negative a-C1q levels were found in 15 of 16 without nephritis. There was a statistically significant positive correlation of the concentration of a-Clq with Ab to double-stranded DNA (a-dsDNA), Ab to nucleosomes, the SLE Disease Activity Index 2000 (SLEDAI-2K), erythrocyturia, hematuria and a negative correlation between a-C1q and complement components C3 and C4. Just after one month of RTM therapy, the patients with nephritis were observed to have a statistically significant decrease in the levels of a-C1q (p=0.002), which persisted 1 year after the treatment (p=0.006). Nineteen patients with the higher baseline concentrations of a-C1q after RTM treatment showed a statistically significant decrease in the levels of a-C1q at 1-, 3-, 6-, and 12-month follow-up (p=0.016, 0.02, 0.035, and 0.04, respectively) which was accompanied by the decreased SLEDAI-2K (p

Anti-Ku antibodies are a special type of myositis-associated antibodies that are characteristic of patients with the overlap syndrome of systemic scleroderma and immune-inflammatory myopathy, as well as occurring in other autoimmune diseases. Patients with these antibodies have their own clinical and laboratory features of the disease and can be identified as a separate anti-Ku syndrome.For the first time in the domestic literature, descriptions of two clinical cases of the development of a cross syndrome associated with anti-Ku antibodies are presented. The features of the course of the disease and the response to various options for immunosuppressive therapy were analyzed.

The article describes a unique clinical case of AL amyloidosis mimicking IgG4-related disease. Plasma cell dyscrasias can mimic clinical and laboratory manifestations of rheumatic diseases, which can lead to a delay in diagnosis and inappropriate therapy.

Objective. To reveal changes of CD+CD25+FoxP3+ T-regulatory cells (T-reg) number in pts with systemic lupus erythematosus (SLE) receiving rituximab and to assess relationship T reg content with changes of disease activity and serum autoantibodies level during treatment. Material and methods. 12 pts with definite SLE were included. Pts were examined before treatment, after 1, 3 and 6 months. Besides routine laboratory tests anti-double-stranded DNA antibodies, B lymphocytes and T reg cells number was evaluated with flow-cytometry. SLE activity was assessed with SLEDAI 2K scale. Rituximab 500 mg was administered every week iv during 4 weeks. 4 pts received combined treatment with cyclophosphan. Results. Mean age of pts was 30,5±9,8 years (Me 31 years, varied from 18 to 49 years), disease duration varied from 7 to 148 months. T reg number before treatment was not decreased and did not correlated with anti-DNA antibodies level. T reg markers (Foxp3+, CD25+, CD4+CD25+) changes and values of SLE activity on SLEDAI 2K after the end of treatment correlated with presence of clinical response to treatment with rituximab in 3 months. Binary logistic regression model including 4 above mentioned predictors in total allows predicting correctly clinical response to therapy in 83% of cases. Conclusion. Changes of CD25+, CD4+CD25+, CD4+CD25+FoxP3+ T-cells number immediately after the end of treatment with rituximab correlated with clinical effect of the treatment and determined subsequent response to anti-B cell therapy.